SUMMARY Individually, dysfunction of both the endoplasmic reticulum (ER) and mitochondria has been linked to aging, but how communication between these organelles might be targeted to promote longevity is unclear. Here, we provide evidence that, in Caenorhabditis elegans , inhibition of the conserved unfolded protein response (UPR ER ) mediator, activating transcription factor ( atf ) -6 , increases lifespan by modulating calcium homeostasis and signaling to mitochondria. Atf-6 loss confers longevity via downregulation of the ER calcium buffer, calreticulin. ER calcium release via the inositol triphosphate receptor (IP 3 R/ itr-1 ) is required for longevity, while IP 3 R/ itr-1 gain of function is sufficient to extend lifespan. Highlighting coordination between organelles, the mitochondrial calcium import channel mcu-1 is also required for atf-6 longevity. IP 3 R inhibition leads to impaired mitochondrial bioenergetics and hyperfusion, which is sufficient to suppress long life in atf-6 mutants. This study reveals the importance of organellar calcium handling as a critical output for the UPR ER in determining the quality of aging.

Individual mitochondria undergo an intermittent, all-or-none electrochemical excitation termed “mitoflash.” Feng et al. show that mitoflash occurs following build-up of mitochondrial electrochemical potential and may serve to autoregulate mitochondrial proton electrochemical potential.

Mitochondrial flashes (mitoflashes) are recently discovered mitochondrial activity which reflects chemical and electrical excitation of the organelle. Emerging evidence indicates that mitoflashes represent highly regulated, elementary signaling events that play important roles in physiological and pathophysiological processes in eukaryotes. Furthermore, they are regulated by mitochondrial ROS, Ca, and protons, and are intertwined with mitochondrial metabolic processes. As such, targeting mitoflash activity may provide a novel means for the control of mitochondrial metabolism and signaling in health and disease. In this brief review, we summarize salient features and mechanisms of biogenesis of mitoflashes, and synthesize data on mitoflash biology in the context of metabolism, cell differentiation, stress response, disease, and ageing.

The mitochondrial unfolded protein response (UPRmt) has emerged as a predominant mechanism that preserves mitochondrial function. Consequently, multiple pathways likely exist to modulate UPRmt. We discovered that the tRNA processing enzyme, homolog of ELAC2 (HOE-1), is key to UPRmt regulation in Caenorhabditis elegans. We find that nuclear HOE-1 is necessary and sufficient to robustly activate UPRmt. We show that HOE-1 acts via transcription factors ATFS-1 and DVE-1 that are crucial for UPRmt. Mechanistically, we show that HOE-1 likely mediates its effects via tRNAs, as blocking tRNA export prevents HOE-1-induced UPRmt. Interestingly, we find that HOE-1 does not act via the integrated stress response, which can be activated by uncharged tRNAs, pointing towards its reliance on a new mechanism. Finally, we show that the subcellular localization of HOE-1 is responsive to mitochondrial stress and is subject to negative regulation via ATFS-1. Together, we have discovered a novel RNA-based cellular pathway that modulates UPRmt.